Premixed Insulin Analogues

Premixed insulin analogues combine a rapid-acting analogue with its protamine-bound intermediate form (biphasic insulin aspart, and mixtures of insulin lispro with insulin lispro protamine) or with insulin degludec (the co-formulation of insulin degludec and insulin aspart). They are given subcutaneously once to three times daily with meals. Compared with premixed human insulin they act faster, control post-meal glucose better and allow dosing at the start of the meal, with similar HbA1c lowering.

Classification. Premixed analogue insulins in fixed ratios: biphasic insulin aspart 30 (30% soluble insulin aspart, 70% insulin aspart protamine); insulin lispro mixtures 25 and 50 (25% or 50% insulin lispro, remainder insulin lispro protamine); insulin degludec and insulin aspart 70 30 (70% degludec, 30% aspart). U100 pens and cartridges.

Mechanism. Bind the insulin receptor with the same effects as human insulin. The rapid component covers the meal and the protaminated or ultra-long component gives basal action.

Pharmacodynamics. Biphasic aspart and lispro mixtures: onset 10 to 20 minutes, a first peak at 1 to 2 hours and a second at 4 to 6 hours, duration 14 to 24 hours. Degludec and aspart co-formulation: onset 10 to 20 minutes, one rapid peak, and a flat basal action over 42 hours.

Pharmacokinetics. Absorption of the rapid fraction is faster than regular insulin; the intermediate fraction (protamine) varies with mixing and site. Cleared by the liver and kidney.

Type 2 diabetes, adults, biphasic insulin aspart 30 or insulin lispro mixtures.

• Start 10 units, or 0.2 to 0.3 unit/kg/day, subcutaneously twice daily, immediately before or within 15 minutes of starting breakfast and the evening meal. Use 6 units twice daily in older adults.
• Or start 6 to 12 units once daily with the evening meal and add a second dose before breakfast, and a third before lunch, when needed.
• Titrate by 2 units every 3 days: the morning dose by the pre-evening meal glucose and the evening dose by the fasting glucose (4 units if glucose is over 10 mmol/L), to a target of 4 to 7 mmol/L before meals. Reduce by 10 to 20% after any hypoglycaemia.

Type 2 diabetes, adults, insulin degludec and insulin aspart co-formulation.

• Start 10 units, or 0.1 to 0.2 unit/kg, subcutaneously once daily with the largest meal; add a second dose with another meal if needed. Titrate by 2 units every 3 to 4 days to fasting and pre-meal glucose.
• Maximum single dose is limited by the pen; no fixed maximum daily dose.

Switching. From premixed human insulin 70 30: unit for unit, with the same schedule. From basal insulin: start with the same number of units as the basal dose, given with the largest meal, then add doses.

Type 1 diabetes. Used only when basal-bolus therapy is not possible, with strict meal timing; the degludec and aspart co-formulation can serve as a once or twice daily basal-bolus component in some patients.

Children. Licensed from 10 to 12 years depending on the product and market; directed by a paediatric diabetes team.

Pregnancy. Used when other options are unavailable; fixed ratios make it hard to match changing needs.

Adjustments.

• Kidney: reduce dose by about 25% when eGFR is 10 to 50 and about 50% when under 10, adjusted to glucose.
• Liver: reduce dose in cirrhosis and acute liver failure.
• Older adults: start at the lower dose and use less strict targets.
• Weight: dose by weight at the start of treatment.

Contraindications. Hypoglycaemia; hypersensitivity to the insulin or an excipient (rare), including protamine.

Hypoglycaemia. The main risk, particularly with skipped meals and in the late afternoon or at night. Treat glucose under 4 mmol/L (70 mg/dL) with 15 to 20 g fast oral glucose and recheck at 15 minutes. For severe hypoglycaemia give intravenous glucose 10% 150 to 200 mL over 15 minutes, or glucagon 1 mg intramuscularly or subcutaneously (0.5 mg for children under 25 kg).

Other serious adverse effects.

• Weight gain; lipohypertrophy at repeated injection sites; rotate sites.
• Rare insulin allergy and injection site reactions; fluid retention with pioglitazone.
• Not for intravenous use or for ketoacidosis.

Common prescribing errors.

• Not resuspending the cloudy mixtures (biphasic aspart and lispro mixtures) before use. The clear degludec and aspart co-formulation needs no resuspension.
• Giving the mixture to a patient who is not about to eat.
• Confusing premixed pens with basal or rapid-acting pens, or confusing the different ratios.
• Using a syringe that does not match the vial concentration, or confusing units with millilitres.

Major interactions.

• Increased hypoglycaemia: sulphonylureas, ACE inhibitors, fibrates, fluoxetine, monoamine oxidase inhibitors, salicylates, alcohol.
• Reduced effect: corticosteroids, thiazides, atypical antipsychotics, oestrogen-containing contraceptives, protease inhibitors, thyroid hormones.
• Beta-blockers mask hypoglycaemia symptoms.
• Pioglitazone and insulin together: fluid retention and heart failure.
• GLP-1 receptor agonists and SGLT2 inhibitors: lower the insulin dose when starting.

Special groups.

• Pregnancy: biphasic insulin aspart has pregnancy data; fixed ratios limit adjustment; needs rise from the second trimester and fall sharply after delivery.
• Breastfeeding: compatible; needs fall in lactation.
• Children: from 10 to 12 years depending on product.
• Older adults: need steady meals; relax targets.
• Kidney impairment: reduce doses; prolonged action.
• Liver impairment: reduce doses.
• East Africa: costlier than premixed human insulin, so limited to those who cannot manage the human mixture or need meal flexibility. Unopened pens keep in a fridge (2 to 8 degrees Celsius); an in-use pen keeps at room temperature up to 30 degrees Celsius for 28 days (56 days for the degludec and aspart co-formulation); protect from direct sunlight and never freeze.

Formulation and preparation. Biphasic insulin aspart and lispro mixtures are cloudy: roll the pen gently between the palms 10 times and tip it up and down until evenly cloudy; do not shake. The degludec and aspart co-formulation is clear. Do not mix with other insulins. Use pens or U100 syringes with U100 vials.

Subcutaneous administration. Inject immediately before the meal, or within 15 minutes of starting it, into the abdomen, thigh or upper arm; rotate sites. Never give intravenously.

Baseline. Capillary glucose, HbA1c, eGFR, hypoglycaemia history, meal pattern.

Monitoring.

• Pre-meal and bedtime capillary glucose during titration.
• HbA1c every 3 months.
• eGFR at least annually.

Dose reduction and stopping. Reduce the dose by 10 to 20% after any hypoglycaemia without a clear cause. Skip a mixture dose if the meal is skipped. Change to a basal-bolus regimen when meals are irregular, hypoglycaemia recurs or total dose is high.

Referral and escalation. Admit severe hypoglycaemia, ketoacidosis or glucose over 25 mmol/L (450 mg/dL) with illness.